1. Technical Field
The invention relates to methods for treating pain, including nociceptive and/or neuropathic pain, and compositions useful in the treatment of pain and pain related conditions. In particular, the methods of the present invention relates to the use of a neuronal nicotinic acetylcholine receptor ligand of formula (I), a pharmaceutically acceptable salt thereof or a composition comprising such compound or salt to treat pain in a subject in need of treatment thereof.
2. Description of Related Technology
Pain is the most common symptom of disease and the most frequent complaint with which patients present to physicians. Pain is commonly segmented by duration (acute vs. chronic), intensity (mild, moderate, and severe), and type (nociceptive vs. neuropathic).
Nociceptive pain is the most well known type of pain, and is caused by tissue injury detected by nociceptors at the site of injury. After the injury, the site becomes a source of ongoing pain and tenderness. Nociceptive pain can be experienced as sharp, dull, or aching. This pain and tenderness are considered “acute” nociceptive pain. This pain and tenderness gradually diminish as healing progresses and disappear when healing is complete. Examples of acute nociceptive pain include surgical procedures (post-op pain), burns, ocular pain, inflammation (due to infection or arthritis) and bone fractures. Even though there may be no permanent nerve damage, “chronic” nociceptive pain results from some conditions when pain extends beyond six months. Examples of chronic nociceptive pain include osteoarthritis, rheumatoid arthritis, and musculoskeletal conditions (e.g., back pain), cancer pain, etc.
Neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” by the International Association for the Study of Pain. Neuropathic pain may refer to peripheral neuropathic pain, which is caused by damage to nerves, or to central neuropathic pain, which is caused by damage to the brain, brainstem, or spinal cord. Neuropathic pain is not associated with nociceptive stimulation, although the passage of nerve impulses that is ultimately perceived as pain by the brain is the same in both nociceptive and neuropathic pain. Neuropathic pain is extremely difficult to manage; it is usually chronic and fails to respond to standard analgesic interventions. Administration of morphine may give some degree of relief but at doses that are impractical for lifelong treatments (Bennett, Hosp. Practice Vol. 33, pages 95 to 114, 1998). The term neuropathic pain encompasses a wide range of pain syndromes of diverse etiologies. The three most commonly diagnosed pain types of neuropathic nature are diabetic neuropathy, cancer neuropathy, and HIV pain. In addition, neuropathic pain is diagnosed in patients with a wide range of other disorders, including fibromyalgia, trigeminal neuralgia, post-herpetic neuralgia, traumatic neuralgia, phantom limb, headaches, as well as a number of other disorders of ill-defined or unknown origin.
Current analgesics fall into two classes, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs are effective for mild to moderate pain with an inflammatory component but are not particularly effective in severe or in chronic neuropathic pain. Further, the use of NSAIDs has been limited by their gastrointestinal side effects. Opioids, such as morphine, are effective in severe acute pain but provide only limited relief in neuropathic pain. In addition, opioids are controlled substances and are limited in their application due to a wide range of side effects including constipation, nausea, cognitive impairment and tolerance issues.
Tricyclic antidepressants and anticonvulsants are also used in the treatment of various pain states, including neuropathic pain. Such drugs typically target the serotonergic and noradrenergic systems and increase the available extracellular levels of both serotonin and norepinephrine. It has been proposed that the postsynaptic activation of α2-adrenoceptors by norepinephrine may be the mechanism through which these compounds alleviate neuropathic pain. However, since antidepressants readily cross the blood-brain barrier, their ability to increase the levels of serotonin and norepinephrine may cause the undesired activation of other receptors leading to the high risk of centrally-mediated side effects. Side effects of antidepressants range from mild but irritating symptoms such as dry mouth and sedation to severe life threatening side effects such as postural hypotension and cardiac arrhythmias. The effectiveness of anticonvulsants in the treatment of various pain states, including neuropathic pain, has also been evaluated (McQuay et al. (1995) Anticonvulsant Drugs For The Management of Pain: A Systematic Review, British Medical Journal 311, 1047-52). Similar to antidepressants, side effects frequently occur with these medications.
Neuronal nicotinic receptors have been targeted for pain and various other central nervous system diseases. See, for example, Vincler, M., Neuronal nicotinic receptors as targets for novel analgesics, Exp. Opin. Invest. Drugs, 2005, 14 (10): 1191-1198; Bunnelle, W. H., Decker, M. W., Neuronal nicotinic acetylcholine receptor ligands as potential analgesics, Exp. Opin. Ther. Patents, 2003, 13 (7): 1003-1021; Decker, M. W., Meyer, M. D., Sullivan, J. P., The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control, Exp. Opin. Invest. Drugs, 2001, 10 (10): 1819-1830. Evidence for analgesic efficacy was first demonstrated by the partial inhibition of nicotine-induced anti-nociception with the α7 antagonists methyllycaconitine (MLA) and α-bungarotoxin. More recently, efficacy for selective α7 agonists has been established in rodent models of peripheral nerve injury. (Damaj, M. Imad et. al., The antinociceptive effects of α7 nicotinic agonists in an acute pain model, Neurophamacology (2000), 39, 2785-2791). The analgesic efficacy of α7 receptor agonists in inflammatory pain models has also been investigated. (Medhurst, S., et al., Activation of the α7-Nicotinic Acetylcholine Receptor Reverses Complete Freund Adjuvant-Induced Mechanical Hyperalgesia in the Rat Via a Central Site of Action. Journal of Pain (2008), 9(7), 580-587.)
Pain is an unmet medical need and the methods and possibilities for treatments of such indications are insufficient. In light of the significance of acute and chronic pain in the lives of many patients, and the limitations in their treatment, it would be beneficial to identify new compositions and methods of treating such disorders, particularly in a manner that reduces adverse ganglionic effects such as at the gastrointestinal systems (e.g. nausea and emesis).